The new study, led by researchers that included Dr. Richard L. Possemato, looked at how cancer cells are able to survive when there鈥檚 a shortage of glucose.
Credit: 好色tv Langone Staff
Laboratory experiments with cancer cells reveal two ways in which tumors evade drugs designed to starve and kill them, a new study shows.
Although chemotherapies successfully treat cancers and extend patients鈥 lives, they are known not to work for everyone for long, as cancer cells rewire the process by which they convert fuel into energy (metabolism) to outmaneuver the drugs鈥 effects. Many of these drugs are so-called antimetabolics, disrupting cell processes needed for tumor growth and survival.
Three such drugs used in the study鈥攔altitrexed, N-(phosphonacetyl)-l-aspartate (PALA), and brequinar鈥攚ork to prevent cancer cells from making pyrimidines, molecules that are an essential component to genetic letter codes, meaning nucleotides, that make up RNA and DNA. Cancer cells must have access to pyrimidine supplies to produce more cancer cells and to produce uridine nucleotides, a primary fuel source for cancer cells as they rapidly reproduce, grow, and die. Disrupting the fast-paced but fragile pyrimidine synthesis pathways, as some chemotherapies are designed to do, can rapidly starve cancer cells and spontaneously lead to them dying (apoptosis).
Led by researchers at 好色tv Langone Health and its Perlmutter Cancer Center, the new study shows how cancer cells survive in an environment made hostile by the persistent shortage of the energy from the glucose (the chemical term for blood sugar) needed to drive tumor growth. This better understanding of how cancer cells evade the drugs鈥 attempts to kill them in a low-glucose environment, the researchers say, could lead to the design of better combination therapies.
, study results showed that the low-glucose environment inhabited by cancer cells, also called the tumor microenvironment, stalls cancer cell consumption of existing uridine nucleotide stores, making the chemotherapies less effective.
Normally, uridine nucleotides would be made and consumed to help make the genetic letter codes and fuel cell metabolism. But when DNA and RNA construction is blocked by these chemotherapies, so, too, is the consumption of uridine nucleotide pools, the researchers found, as glucose is needed to change one form of uridine, UTP, into another usable form, UDP-glucose. The irony, researchers say, is that a low-glucose tumor microenvironment is in turn slowing down cellular consumption of uridine nucleotides and presumably slowing down rates of cell death. Researchers say cancer cells need to run out of pyrimidine building blocks, including uridine nucleotides, before the cells will self-destruct.
In other experiments, low-glucose tumor microenvironments were also unable to activate two proteins, BAX and BAK, sitting on the surface of mitochondria, cells鈥 fuel generators. Activation of these trigger proteins disintegrates the mitochondria and instantly sets off a series of caspase enzymes that help initiate apoptosis.
鈥淥ur study shows how cancer cells manage to offset the impact of low-glucose tumor microenvironments, and how these changes in cancer cell metabolism minimize chemotherapy鈥檚 effectiveness,鈥 said study lead investigator Minwoo Nam, PhD, a postdoctoral fellow in the at 好色tv Grossman School of Medicine and Perlmutter Cancer Center.
鈥淥ur results explain what has until now been unclear about how the altered metabolism of the tumor microenvironment impacts chemotherapy: low glucose slows down the consumption and exhaustion of uridine nucleotides needed to fuel cancer cell growth and hinders resulting apoptosis, or death, in cancer cells,鈥 said senior study investigator . Dr. Possemato is an associate professor in the Department of Pathology and also a member of Perlmutter Cancer Center.
Dr. Possemato, who is also co-leader of the at Perlmutter Cancer Center, says his team鈥檚 study results could one day be used to develop chemotherapies or combination therapies that would change or trick cancer cells into responding the same way in a low-glucose microenvironment as they would in an otherwise stable glucose microenvironment.
He also says that diagnostic tests could be developed to measure how a patient鈥檚 cancer cells would most likely respond to low-glucose microenvironments and to predict how well a patient might respond to a particular chemotherapy.
Dr. Possemato says his team has plans to investigate how blocking other cancer cell pathways might trigger apoptosis in response to these chemotherapies. Some experimental drugs, such as Chk-1 and ATR inhibitors, might accomplish this, he notes, but more need to be investigated, because Chk-1 and ATR inhibitors are not well tolerated by patients.
For the study, researchers performed a scan of 3,000 cancer cell genes known to be involved in cell metabolism to determine, by deletion, which were necessary for cancer cell survival after chemotherapy. Most of the genes they found that were essential to cell survival in low-glucose tumor environments were also involved in pyrimidine synthesis, a precise biological pathway targeted by many chemotherapies. This focused their experiments on how different lab-grown clones of cancer cells responded to low-glucose after chemotherapy and what other chemical processes were impacted by depressed sugar levels.
Funding support for the study was provided by National Institutes of Health grants P30CA016087, R01CA286141, R01CA214948, R01GM132491, and R35GM139610. Additional funding support came from the Pew Charitable Trusts, the Alexander and Margaret Stewart Trust, and the American Cancer Society.
Besides Dr. Nam and Dr. Possemato, other 好色tv Langone researchers involved in this study are co-investigators Wenxin Xia, Abdul Hannan Mir, and .
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